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Objective: The aim of our study was that to assess the allelic and genotype frequencies of nine prothrombotic gene variants in patients with a history of pregnancy loss and recurrent pregnancy loss (RPL). Women who underwent assisted reproductive technology (ART) with ongoing pregnancy and those with recurrent implantation failure (RIF) were also included., Methods: Nine prothrombotic gene variants were evaluated: factor V Leiden (FVL), factor V, H1299R variant (FVR2), factor II (FII) G20210A, methylene-tetrahydrofolate reductase (MTHFR) C677T and A1298C, beta-fibrinogen -455G>A, factor XIII (FXIII) V34L, human platelet antigen-1 (HPA-1) L33P variants, and plasminogen activator inhibitor-1 (PAI-1) 4G/5G. The following study groups were assessed: (1) women who experienced one (n = 334) or two (n = 264) episodes of pregnancy loss; (2) 468 women who experienced RPL; (3) 214 women who underwent ART followed by ongoing pregnancies; and (4) 282 women who experienced RIF after ART, that is, three or more consecutive implantation failures following high-quality embryo transfers to the uterus with an appropriate endometrium. As control group, 430 subjects from the general population were enrolled., Results: FVL, the -455G>A variant of beta-fibrinogen, and PAI-1 4G were associated with a higher risk of developing RPL compared with the general population. Furthermore, FVL, FVR2, FII G20210A and MTHFR C677T conferred a significantly higher risk of RIF in women who performed ART compared with the general population. No statistical differences between the general population and other study groups were observed., Conclusions: Specific prothrombotic genetic variants are more frequently expressed in women with RPL and RIF, supporting their role in the development of polimicrothrombosis and impairing the invasion during embryo implantation., (© 2023 The Authors. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and Obstetrics.)

Background and Objectives: Fractional CO 2 laser has been proposed as an effective treatment for the genitourinary syndrome of menopause (GSM). However, the effects of laser treatment on vulvar tissue have never been assessed. We aimed to assess histological changes related to fractional CO 2 laser in vulvar tissue from GSM patients., Study Design/materials and Methods: A single-center observational prospective cohort study was performed enrolling all GSM patients from July 2017 to October 2018. Patients underwent three outpatient vulvovaginal applications of fractional CO 2 laser and vulvar biopsy before and after treatment. Rates of histological changes in vulvar tissue, the difference in means of Vulva Health Index (VuHI), Vaginal Health Index (VHI), Visual Analogue Scale scores for GSM symptoms, and procedure-related pain, and rate of patient's overall satisfaction with treatment were assessed. Univariate comparisons between continuous variables were performed by using the paired t-test (α error = 0.05)., Results: Of 20 enrolled patients, 18 underwent all laser applications, and 15 underwent both vulvar biopsies. 93.3% of patients showed remodeling of vulvar connective tissue; 80% showed improvement in vulvar epithelium trophism and 86.7% showed neovascularization. Differences in means between before and after treatment were significant for VuHI, VHI, and all GSM symptoms. Means ± standard deviation of the degree of pain at each laser application were 4.4 ± 0.9, 3.7 ± 1.6, and 2.9 ± 1.9. The rate of overall satisfaction with the treatment was 72.2%., Conclusions: Fractional CO 2 laser leads to a restoration of the normal architecture of vulvar tissue, with significant improvement in GSM-related signs and symptoms, and overall satisfaction with the treatment in most GSM patients. Lasers Surg. Med. © 2020 Wiley Periodicals LLC., (© 2020 Wiley Periodicals LLC.)

Study Objective: To compare the tolerability and diagnostic accuracy of virtual ultrasonographic hysteroscopy (VUH) with that of conventional diagnostic outpatient hysteroscopy in the workup of patients who are infertile., Design: A single-center, retrospective cohort study., Setting: Department of Obstetrics and Gynecology, Gynecologic Oncology, and Minimally Invasive Pelvic Surgery Unit of Sacred Heart Hospital Don Calabria in Negrar, Italy., Patients: A total of 120 consecutive women who underwent hysterosalpingosonography and subsequent VUH and conventional hysteroscopy for infertility evaluation were included. The inclusion criterion was infertility for at least 1 year, with evaluation in the early or intermediate follicular phase of the menstrual cycle., Interventions: After the placement of an intracervical catheter, a Ringer Lactate solution was injected into the uterine cavity and fallopian tubes, and a 3D volume was obtained. The ultrasound volume acquired was successively elaborated offline, and a VUH was performed. Subsequently, a variable amount of air was introduced into the uterine cavity, and the patency of the salpinges was evaluated., Measurements and Main Results: The VUH findings were compared with those of conventional hysteroscopy performed in the subsequent month. For the detection of endometrial pathology in the overall pool, the sensitivity and specificity of VUH in comparison with conventional hysteroscopy were 100% (95% confidence interval [CI], 84.6%-100%) and 100% (95% CI, 96.3%-100%), respectively. For the detection of uterine cavity pathology and uterine malformations in the overall pool, the sensitivities of VUH were 80% (95% CI, 28.4%-99.5%) and 100% (95% CI, 75.3%-100%), respectively, with specificities of 100% (95% CI, 96.8%-100%) and 100% (95% CI, 96.6%-100%), respectively, when compared with conventional hysteroscopy. The positive predictive values for endometrial pathology, uterine cavity alterations, and uterine malformations were 100% (95% CI, 84.6%-100%), 100% (95% CI, 39.8%-100%), and 100% (95% CI, 75.3%-100%), respectively, with a receiver operating characteristic area of 100%, 90% (95% CI, 70%-100%), and 100%, respectively. There were no cases of severe vasovagal reactions or other complications. Most patients (67%, 81 of 120 women) described the examination as "less painful than expected," 25% (30 of 120 women) "just as expected," and only 7% (9 of 120 women) as "more painful than expected.", Conclusion: VUH was well tolerated and showed a high accuracy (100%) in the study of the uterine cavity when compared with conventional hysteroscopy., (Copyright © 2020. Published by Elsevier Inc.)

Atypical polypoid adenomyoma (APA) is a rare uterine lesion constituted by atypical endometrioid glands, squamous morules, and myofibromatous stroma. We aimed to assess the immunophenotype of the 3 components of APA, with regard to its pathogenesis and its differential diagnosis. A systematic review was performed by searching electronic databases from their inception to January 2019 for immunohistochemical studies of APA. Thirteen studies with 145 APA cases were included. APA glands appeared analogous to atypical endometrial hyperplasia (endometrioid cytokeratins pattern, Ki67≤50%, common PTEN loss, and occasional mismatch repair deficiency); the prominent expression of hormone receptors and nuclear β-catenin suggest that APA may be a precursor of "copy number-low," CTNNB1-mutant endometrial cancers. Morules appeared as a peculiar type of hyperdifferentiation (low KI67, nuclear β-catenin+, CD10+, CDX2+, SATB2+, p63-, and p40-), analogous to morular metaplasia in other lesions and distinguishable immunohistochemically from both conventional squamous metaplasia and solid cancer growth. Stroma immunphenotype (low Ki67, α-smooth-muscle-actin+, h-caldesmon-, CD10-, or weak and patchy) suggested a derivation from a metaplasia of normal endometrial stroma. It was similar to that of nonatypical adenomyoma, and different from adenosarcoma (Ki67 increase and CD10+ in periglandular stroma) and myoinvasive endometrioid carcinoma (h-caldesmon+ in myometrium and periglandular fringe-like CD10 pattern).

In the management of women diagnosed with endometrial hyperplasia (EH), it is crucial to determine the risk of coexistent cancer. Diabetes mellitus has been recently suggested as a significant risk factor. However, results in this regard are conflicting. Our aim was to assess the association between diabetes mellitus and coexistent cancer in women diagnosed with endometrial hyperplasia. A systematic review and meta-analysis was performed by searching electronic databases from their inception to October 2018 for studies assessing the presence of coexistent cancer after a preoperative diagnosis of endometrial hyperplasia in women stratified for diabetes mellitus. Odds ratio was calculated with 95% confidence interval; a p value <0.05 was considered significant. Twelve retrospective studies with 1579 EH were included. Diabetes mellitus showed significant association with the presence of cancer coexistent with endometrial hyperplasia (OR = 1.96; 95% CI, 1.07-3.60; p = 0.03). Heterogeneity among studies was moderate (I 2  = 55%). Funnel plot showed asymmetric distribution of OR values, with the large and accurate studies showing results stronger than small and less accurate one; this finding should exclude a publication bias. In women diagnosed with endometrial hyperplasia, diabetes mellitus is a risk factor for coexistent cancer, and thus may be included in a predictive algorithm for the risk stratification. In women conservatively treated, glycemic control may be required to prevent the risk of progression. Further studies are necessary to confirm the clinical significance of diabetes mellitus in this field.

Objective: The objective of this study was to evaluate the efficacy of rescue fractional microablative CO2 laser treatment in women with severe symptoms and sexual dysfunction related to lichen sclerosus not responsive to long-term ultra-potent topical corticosteroid treatment., Methods: Consecutive eligible women with lichen sclerosus referred to our unit who received fractional microablative CO2 laser treatment after failure of ultra-potent topical corticosteroid treatment were enrolled in the study. The diagnosis was confirmed by histological assessment in all cases. Patients underwent two cycles of CO2 laser every 30 to 40 days. The severity of lichen sclerosus-related symptoms, sexual function, and procedure discomfort were evaluated with a visual analog scale in the same individual at baseline, after completion of each treatment cycle. Follow-up visits were scheduled during each treatment cycle and at least 1 month after completion of the treatment. The Friedman ANOVA test was used to evaluate differences in the visual analog scale scores of each symptom during treatment., Results: A total of 100 patients with vulvar lichen sclerosus were screened, 40 of whom fulfilled the eligibility criteria. We found a significant improvement in vulvar itching (χ [2] = 31,182, P < 0.001), vulvar dryness (χ [2] = 40,364, P < 0.001), superficial dyspareunia (χ [2] = 37,488, P < 0.001), and sensitivity during intercourse (χ [2] = 22,143, P < 0.001) after two CO2 laser cycles. Pain related to probe movement and laser application was low and did not change significantly consequent to treatment. No systemic or local adverse effects occurred during or after laser treatment., Conclusion: Fractional microablative CO2 laser treatment is safe and might represent an effective rescue procedure for patients suffering from lichen sclerosus who fail to respond to long-term ultra-potent topical corticosteroid treatment. These preliminary findings require further study with adequately powered randomized controlled trials.

Objective: The conservative treatment of endometrial hyperplasia without atypia (HWA), atypical endometrial hyperplasia (AH/EIN) and early endometrioid carcinoma (EEC) is based on progestins. We aimed to assess whether diabetes mellitus affects the responsiveness of HWA, AH/EIN and EEC to conservative treatment, through a systematic review and meta-analysis. Study design: Electronic databases were searched for studies assessing the outcome of conservative treatment in HWA, AH/EIN and EEC, stratified based on the diagnosis of diabetes mellitus. The association of diabetes mellitus with treatment failure was assessed by using odds ratio (OR). A p -value  < .05 was considered significant. The risk of publication bias was assessed by using a funnel plot. A subgroups analyses was performed based on histologic diagnosis of benignity (HWA) or premalignancy/malignancy (AH/EIN or EEC). Results: Six studies with 876 patients (383 HWA, 365 AH/EIN and 128 EEC) were included. Overall, diabetes mellitus was not associated with outcome of treatment (OR = 1.20; p  = .62). The association was not significant in both the HWA subgroup (OR = 0.95; p  = .93) and in AH/EIN and EEC subgroup (OR = 1.43; p  = .46). There was no significant risk of publication bias. Conclusions: Diabetes mellitus does not affect the outcome of conservative treatment in HWA, AH/EIN and EEC.

Background: In the 2014 WHO classification of endometrial hyperplasia (EH), complex EH is lumped together with simple EH in the benign category of non-atypical EH., Objective: To assess the risk of coexistent cancer in complex EH and simple EH without atypia, through a systematic review and meta-analysis., Methods: Electronic databases were searched from their inception to January 2019 for relevant articles., Results: Twelve studies assessing a total of 804 non-atypical EH were included. The risk of coexistent cancer was significantly higher in complex EH (12.4%) than in simple EH (2%), with an OR of 6.03 (p = 0.0002)., Conclusion: Even in the absence of cytologic atypia, complex EH is associated with a significant risk of coexistent cancer. Further studies are necessary to investigate the need for a revision in the WHO classification.

Introduction: Progestogens are widely used for the conservative treatment of endometrial hyperplasia and early endometrial cancer. Nevertheless, they do not achieve the regression in all cases. Although several immunohistochemical markers have been assessed to predict the response to treatment, their usefulness is still unclear. We aimed to analyze the usefulness of each immunohistochemical marker studied in predicting the response to progestogens in endometrial hyperplasia and early endometrial cancer., Material and Methods: Electronic databases were searched for relevant articles from January 2000 to June 2018. All studies assessing the association of immunohistochemical markers with the outcome of the progestogen-based therapy in endometrial hyperplasia and early endometrial cancer were included. The expression of immunohistochemical markers in pretreatment phase and changes of expression during the follow-up were evaluated in relation to response to therapy and relapse., Results: Twenty-seven studies with 1360 women were included in the systematic review; 43 immunohistochemical markers were assessed. The most studied predictive markers in the pretreatment phase were progesterone and estrogen receptors, although with conflicting results; their isoforms, and in particular progesterone receptor B, appeared more promising. Further studies are needed to confirm the usefulness of mismatch repair proteins, Dusp6, GRP78 and PTEN combined with other molecules such as phospho-AKT or phospho-mTOR. In the follow-up phase, Nrf2 and survivin showed the stronger evidence; a role may also be played by Bcl2 and Ki67. Further studies are necessary for Fas, NCoR, AKR1C1, HE4, PAX2 and SPAG9., Conclusions: Several immunohistochemical markers might be helpful in predicting the response to conservative treatment of endometrial hyperplasia and early endometrial cancer on pretreatment and follow-up specimens. Further studies are needed to confirm their usefulness and possibly integrate them in a predictive immunohistochemical panel., (© 2019 Nordic Federation of Societies of Obstetrics and Gynecology.)

Introduction: Progestins are used as conservative treatment of endometrial hyperplasia (EH) and early endometrial cancer (EEC). We aimed to assess whether immunohistochemical expression of estrogens and progesterone receptors (ER and PR) predicts the treatment response., Material and Methods: Electronic databases were searched for studies assessing ER and PR expression in EH and EEC treated with progestins. Relative risk for poor response, sensitivity, specificity, diagnostic odds ratio positive and negative likelihood ratios (LR + and LR - ) and area under the curve (AUC) on summary receiver operating characteristic curve were calculated. Subgroup analyses were based on administration route (oral progestin or levonorgestrel-intrauterine device) and on histological diagnosis (atypical EH/EEC or non-atypical EH). Only high accuracy (AUC > 0.9; LR +  >10; LR -  <0.1) was considered determining for the clinical practice., Results: Thirteen studies with 635 patients were included in the systematic review. Studies at high risk of bias were excluded from the meta-analysis. Negative ER expression did not significantly predict poor response (P = 0.16), with low predictive accuracy (AUC = 0.637). Negative PR significantly predicted poor response (P = 0.01), with moderate accuracy (AUC = .806). In the oral progestin subgroup, neither ER (P = 0.55) nor PR (P = 0.18) had significant predictive value. In the levonorgestrel-intrauterine device subgroup, both ER (P < 0.0001) and PR (P = 0.02) were significantly predictive of good response, although the accuracy was suboptimal (LR + 6.02 and 2.48, respectively; LR - 0.59 and 0.55, respectively). The atypical EH/EEC subgroup showed non-significant results. Data about non-atypical EH were not extractable., Conclusions: ER and PR expressions are significantly predictive of response in EH and EEC treated with a levonorgestrel-intrauterine device but not with oral progestins. However, their accuracy is insufficient to be determining in the clinical practice., (© 2019 Nordic Federation of Societies of Obstetrics and Gynecology.)

Introduction: Atypical polypoid adenomyoma is an uncommon uterine lesion which can coexist with endometrial atypical hyperplasia and/or cancer. Atypical polypoid adenomyoma affects premenopausal women in most cases, but it shows high recurrence rate if conservatively treated. To date, the management of patients is based on low-quality evidence and is not standardized. Our primary aim was to explore the optimal management of atypical polypoid adenomyoma, with particular regard to the fertility-sparing approach. The secondary aim was to define clinicopathologic features of atypical polypoid adenomyoma., Material and Methods: Medline, Embase, Web of Sciences, Scopus, ClinicalTrial.gov, OVID, Google Scholar and Cochrane Library were searched for studies reporting outcomes of atypical polypoid adenomyoma treatments. Univariate comparisons among outcomes of fertility-sparing treatments (rates of initial response, progression, recurrence, final complete response, pregnancy) were performed with Fisher's exact test (α = .05)., Results: Eleven retrospective studies with 237 patients were included; 85.5% of patients were premenopausal and 62.9% were nulliparous. Atypical polypoid adenomyoma coexisted with atypical hyperplasia in 5.5% of cases and with endometrial cancer in 5.9%. Overall risks of recurrence and progression to cancer were 28.9% and 16.6%, respectively. Fertility-sparing treatments included hormonal therapy with or without maintenance, hysteroscopic transcervical resection, dilation and curettage, and hormonal therapy combined with transcervical resection or dilation and curettage. Transcervical resection showed significantly higher initial response rates (P from <0.001 to 0.023) than any other treatment. Transcervical resection and transcervical resection+hormonal therapy showed significantly lower progression rates (P < 0.001), and higher final complete response rates (P < 0.001) than any other treatment. No significant differences were found in the rates of pregnancy (P = 0.533 - 0.647) or recurrence (P = 0.052 - 0.475). Among the different transcervical resection techniques, the 4-step transcervical resection showed significantly lower rates of progression (P = 0.002) and recurrence (P = 0.013) than other techniques. Limitations to our results were the retrospective design of the studies and the relatively small sample size, due to the rarity of atypical polypoid adenomyoma., Conclusions: Based on its effectiveness and safety, transcervical resection may be the first-line fertility-sparing treatment for atypical polypoid adenomyoma. In particular, 4-step transcervical resection showed the best results. Given the risk of recurrence, progression and coexistent atypical hyperplasia or cancer, follow-up biopsies are advisable. When fertility preservation is not required, hysterectomy might be advisable., (© 2019 Nordic Federation of Societies of Obstetrics and Gynecology.)

POSEIDON groups 1 and 2 patients respond poorly (<4 oocytes retrieved) or sub-optimally (4-9 oocytes retrieved) to gonadotropin stimulation despite the presence of adequate ovarian parameters, which negatively affect their cumulative chances of delivering a baby using Assisted Reproductive Technology. A polygenic trait involving gonadotropins and/or their receptors seems to be the primary pathophysiology mechanism explaining this phenomenon. The clinical management is mainly focused on maximizing oocyte yield as to increase the likelihood of having at least one euploid embryo for transfer. Indices such as FORT (follicle output rate) and FOI (follicle-to-oocyte index) may be used to determine if the ovarian reserve was properly explored during a previous ovarian stimulation. Testing for the presence of common polymorphisms affecting gonadotropins and/or their receptors can also be considered to identify patients at risk of hypo-response. An individualized estimation of the minimum number of oocytes needed to obtain at least one euploid embryo can assist counseling and treatment planning. Among currently existing pharmacological interventions, use of recombinant FSH in preference over urinary gonadotropin preparations, FSH dosage increase, and use of rLH supplementation may be considered -alone or combined- for optimally managing POSEIDON's groups 1 and 2 patients. However, given the recent introduction of the POSEIDON criteria, there is still a lack of studies examining the role of interventions specifically to patients classified as groups 1 and 2, thus making it an area for open research.

The purpose of a pharmacogenomic approach is to tailor treatment on the basis of an individual human genotype. This strategy is becoming increasingly common in medicine, and important results have been obtained in oncologic and antimicrobial therapies. The rapid technological developments and availability of innovative methodologies have revealed the existence of numerous genotypes that can influence the action of medications and give rise to the idea that a true "individualized" approach could become in the future a reality in clinical practice. Moreover, compared to the past, genotype analyses are now more easily available at accessible cost. Concerning human reproduction, there is ample evidence that several variants of gonadotropins and their receptors influence female reproductive health and ovarian response to exogenous gonadotropins. In more detail, variants in genes of follicle-stimulating hormone β -chain (FSH-B) and its receptor (FSH-R) seem to be the most promising candidates for a pharmacogenomic approach to controlled ovarian stimulation in assisted reproductive technologies. In the present review, we summarize the evidence regarding FSH-B and FSH-R variants, with special reference to their impact on reproductive health and assisted reproductive technology treatments.

The 2014 World Health Organization (WHO) classification of endometrial hyperplasia (EH) defines premalignant EH based on only cytologic atypia, disregarding architecture complexity. We aimed to assess the impact of architecture complexity on the risk of cancer in non-atypical EH. A systematic review and meta-analysis was performed by searching electronic databases form their inception to October 2018. All studies assessing the rates of progression to cancer in non-atypical EH (simple vs complex) were included. Pooled relative risk (RR) for cancer progression was calculated; a p-value < 0.05 was considered significant. Eight studies with 1066 women were included. The risk for progression of non-atypical EH to cancer was significantly higher in complex EH than in simple EH (p < 0.0001), with an RR of 4.90. In conclusion, the complexity of glandular architecture significantly increases the risk of cancer in non-atypical EH. Complex non-atypical EH may be regarded as a low-risk premalignant lesion rather than a benign condition., (© 2019 APMIS. Published by John Wiley & Sons Ltd.)

Purpose: Rates of progression of endometrial hyperplasia (EH) to endometrial cancer (EC) are highly variable. Among several prognostic markers, PTEN has been recommended by ESMO-ESGO-ESTRO to identify premalignant EH. However, its prognostic accuracy is unclear. Thus, we aimed to assess: (1) the association between PTEN loss in EH and risk of cancer, and (2) the prognostic accuracy of PTEN immunohistochemistry in EH., Methods: Electronic databases were searched from their inception to June 2018. All studies assessing PTEN immunohistochemistry in EH and the presence of EC on subsequent hysterectomy were included. Odds ratio (OR), sensitivity, specificity, positive and negative predictive value (PPV and NPV), positive and negative likelihood ratio (LR + and LR-) and area under the curve (AUC) on SROC curves were calculated with subgroup analysis (short/long-term; atypical/non-atypical EH)., Results: Nine retrospective studies assessing 933 EH were included. PTEN loss in EH was significantly associated with increased risk of EC (OR = 3.32, p = 0.001). The association was significant only on the short term ( < 1 year) (OR = 3.45, p = 0.002) and in atypical EH (OR = 1.89, p = 0.01). For overall analysis and short-term/atypical EH subgroup the prognostic accuracy was low, with sensitivity = 0.58 and 0.68, specificity = 0.60 and 0.48, VPp = 0.41 and 0.54, VPN = 0.75 and 0.63, LR +  = 1.80 and 1.37, LR - =  0.62 and 0.56, AUC = 0.687 and 0.721, respectively., Conclusion: PTEN loss in EH is a risk factor for EC, but is not reliable in predicting the risk of EC. In atypical EH, PTEN loss is associated with a risk of concurrent EC of over 50%. This information might integrate the patients' informed consent for the choice of treatment (conservative/hysterectomy), especially in borderline cases. In conservative approach, PTEN loss might suggest closer follow-up.

Purpose: Benign and precancerous endometrial hyperplasias (EH) are differentiated thorough two possible histomorphologic classifications: WHO (adopting the subjective evaluation of cytologic atypia) and EIN (adopting several histomorphologic parameters, evaluable subjectively, or objectively with a computerized analysis calculating a prognostic score, the D score). ACOG recommends the use of EIN system although no distinction was made between objective assessment (not widely available), and subjective assessment (more applicable in the common practice). Moreover, it is still unclear if subjective EIN system is actually preferable to WHO classification. We aimed to assess the reliability of WHO system, D score and subjective EIN system in stratifying the risk of progression to cancer in EH., Methods: MEDLINE, EMBASE, Web of Sciences, Scopus, ClinicalTrial.gov, OVID, Cochrane Library and Google Scholar were searched for relevant articles from the inception to August 2018. All studies assessing the rates of progression of EH to cancer were included., Results: Twelve cohort studies and one case-control study, assessing 3629 EH, were included. Relative risk (RR) for cancer progression was calculated with 95% confidence interval (CI), and results were compared using Chi-square test (significant p value < 0.05). WHO system showed a RR of 8.74 (95% CI 6.66-11.47). Objective D score showed a RR of 29.22 (95% CI 13.24-64.51), significantly higher than WHO (p = 0.005). Subjective EIN system showed a RR of 19.37 (95% CI 5.86-64.01), intermediate between WHO and D score, without significant differences (p = 0.20 and p = 0.57, respectively)., Conclusion: Objective EIN criteria with D score are significantly more reliable than WHO criteria in stratifying the risk of progression of EH to cancer. Subjective EIN criteria did not show significant superiority over WHO instead. Further studies are necessary to determine if subjective EIN system should replace WHO system in the routine diagnosis of EH.

Study Objective: To evaluate safety and effectiveness of the combination of hysteroscopic endometrial focal resection with levonorgestrel-releasing intrauterine device (LNG-IUD) for International Federation of Gynecology and Obstetrics stage IA G1 early endometrial cancer (EEC) and atypical endometrial hyperplasia (AEH) in young women to preserve their fertility., Design: Retrospective case series (Canadian Task Force classification II-3)., Setting: University Federico II, Naples, Italy., Patients: The medical records of 69 consecutive patients treated from 2007 to 2017 with diagnosis of EEC (n = 14) or AEH (n = 55) meeting inclusion criteria were reviewed., Interventions: Patients with focal EEC were treated by hysteroscopic resection of the lesion according to Mazzon's technique; patients with AEH were treated by superficial endometrial resection, preserving the basal layer of the endometrium. An LNG-IUD was inserted in all patients after surgery. Patients were followed for 24 months with serial hysteroscopic biopsies., Measurements and Main Results: Rates of response, live birth, and recurrence were assessed. Of the 14 patients with EEC, 11 (78.6%) achieved a complete response, 2 (18.2%) of whom had subsequent relapse, 1 (7.1%) showed partial response, whereas 2 (14.3%) were nonresponders (1 stable disease and 1 progression). Of the 55 patients with AEH, 51 (92.7%) achieved a complete response, 2 (3.9%) of whom had subsequent relapse, 3 (5.5%) showed partial response, whereas only 1 (1.8%) was nonresponder with stable disease. Among 25 patients who had removed the LNG-IUD, 10 (40%) gave birth after natural conception in the last 12 months of follow-up., Conclusion: The combination of hysteroscopic resection with an LNG-IUD as fertility-sparing treatment of EEC and AEH showed similar response and live birth rates compared with those reported in literature for progestins alone, but with considerably lower relapse rate. We advocate the use of this combined approach as an alternative fertility-sparing option in patients with ECC and AEH., (Copyright © 2018 AAGL. Published by Elsevier Inc. All rights reserved.)

Objectives: CTNNB1 exon 3 mutations have shown independent prognostic value in endometrial cancer. We aimed to assess whether nuclear β-catenin expression is an accurate surrogate, as immunohistochemistry is cheaper, faster, and more widely applicable than sequencing., Methods: A systematic review was performed by searching electronic databases for all studies assessing the association between β-catenin immunohistochemical expression and CTNNB1 mutations. Meta-analysis of diagnostic accuracy was performed by calculating sensitivity, specificity, positive and negative likelihood ratios (LR+ and LR-), diagnostic odds ratio (DOR), and area under the curve (AUC) on summary receiver operating characteristic curves., Results: Fifteen observational studies with 1,158 endometrial carcinomas were included. Pooled estimates showed sensitivity = 0.88, specificity = 0.85, LR+ = 4.57, LR- = 0.20, DOR = 27.16, and high diagnostic accuracy (AUC = 0.91)., Conclusions: Nuclear expression of β-catenin is an accurate immunohistochemical surrogate of CTNNB1 exon 3 mutations and thus might be considered in the risk stratification of endometrial cancer., (© American Society for Clinical Pathology, 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Guidelines recommend protein phosphatase and tensin homolog (PTEN) immunohistochemistry for differentiating between benign endometrial hyperplasia (BEH) and atypical endometrial hyperplasia/endometrioid intraepithelial neoplasia (AEH/EIN). However, it is unclear when PTEN expression should be defined as 'lost' and thus suggestive of AEH/EIN. We aimed to determine the optimal immunohistochemical criteria to define PTEN loss in endometrial hyperplasia, through a systematic review and meta-analysis of diagnostic accuracy. Electronic databases were searched for studies assessing immunohistochemical expression of PTEN in both BEH and AEH/EIN specimens. PTEN status ('loss' or 'presence') was the index test; histological diagnosis ('AEH/EIN' or 'BEH') was the reference standard. Accuracy was quantified based on the area under the curve (AUC) on summary receiver operating characteristic (SROC) curves, for several different thresholds of PTEN expression. Eighteen studies with 1362 hyperplasias were included. Six different criteria to define PTEN loss were assessed. Low diagnostic accuracy was found for complete loss of expression (AUC = 0.71), presence of any null gland (AUC = 0.63), positive cells <10% (AUC = 0.64), positive cells <50% (AUC = 0.71) and moderate-to-null intensity (AUC = 0.64). Barely moderate diagnostic accuracy was only found for the subjective criterion 'weak-to-null intensity' (AUC = 0.78). Therefore, the clinical usefulness of PTEN immunohistochemistry in this field should be further investigated., (© 2019 APMIS. Published by John Wiley & Sons Ltd.)

Endometrial hyperplasia (EH) is classified into benign and precancerous according to two different histomorphological systems: the World Health Organisation (WHO) system (based on the subjective evaluation of cytological atypia) and the endometrial intraepithelial neoplasia (EIN) system (based on a combination of several parameters that are assessable subjectively, or objectively through computerised analysis). The American College of Obstetricians and Gynecologists recommends use of the EIN system. Nonetheless, a higher prognostic value for EIN criteria was demonstrated only with the objective assessment, which is not routinely applicable. The aim of this study was to evaluate which of the subjective classifications of EH (WHO or EIN) has better prognostic value, by assessing the risk of coexistent cancer. Electronic databases were searched for relevant articles from the inception of the databases to July 2018. All studies assessing the presence of cancer on hysterectomy specimens after a preoperative histological diagnosis of EH were included. Odds ratios (ORs), sensitivity and specificity were calculated with 95% confidence intervals (CIs). Sixteen cohort studies and three case-control studies, assessing 2582 EHs, were included. The WHO criteria showed an OR of 11.15 (95% CI 7.65-16.24), a sensitivity of 0.86 (95% CI 0.82-0.90) and a specificity of 0.67 (95% CI 0.64-0.70) for coexistent cancer. The subjective EIN system showed a similar OR (11.85, 95% CI 4.91-28.62; P = 0.90), higher sensitivity (0.98, 95% CI 0.94-0.99), and lower specificity (0.29, 95% CI 0.24-0.34). The WHO system and the subjective EIN system have similar prognostic values. However, the EIN criteria appear to be more sensitive and thus more suitable for selecting women who need to be treated, whereas the WHO criteria, based on cytological atypia, seem to be more specific for lesions at higher risk of cancer. Therefore, integration of the EIN system with cytological atypia should be considered., (© 2018 John Wiley & Sons Ltd.)

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Introduction: Endometrial hyperplasia may be either a benign proliferation or a premalignant lesion. In order to differentiate these two conditions, two possible histologic classifications can be used: the World Health Organization (WHO) classification and the endometrial intraepithelial neoplasia (EIN) classification. The 2017 European Society of Gynaecological Oncology guidelines recommend the use of immunohistochemistry for tumor suppressor protein phosphatase and tensin homolog (PTEN) to improve the differential diagnosis. Nonetheless, its diagnostic accuracy has never been defined. We aimed to assess the diagnostic accuracy of immunohistochemistry for PTEN in the differential diagnosis between benign and premalignant endometrial hyperplasia., Material and Methods: Electronic databases were searched from their inception to May 2018 for studies assessing immunohistochemical expression of PTEN in endometrial hyperplasia specimens. PTEN status ("loss" or "presence") was the index test; histological diagnosis ("precancer" or "benign") was the reference standard. Sensitivity, specificity, positive and negative likelihood ratios (LR+, LR-), diagnostic odds ratio (DOR), and area under the curve (AUC) on summary receiver operating characteristic curves were calculated (95% CI), with a subgroup analysis based on the histologic classification adopted (WHO vs EIN)., Results: Twenty-seven observational studies with 1736 cases of endometrial hyperplasia were included. Pooled estimates showed low diagnostic accuracy: sensitivity 54% (95% CI 50%-59%), specificity 66% (63%-69%), LR+ 1.55 (1.29-1.87), LR- 0.72 (0.62-0.83), DOR 3.56 (2.02-6.28), AUC 0.657. When the WHO subgroup was compared with the EIN subgroup, higher accuracy (AUC 0.694 vs. 0.621), and higher heterogeneity in all analyses, were observed., Conclusions: Immunohistochemistry for PTEN showed low diagnostic usefulness in the differential diagnosis between benign and premalignant endometrial hyperplasia. In the absence of further evidence, the recommendation about its use should be reconsidered., (© 2018 Nordic Federation of Societies of Obstetrics and Gynecology.)

Introduction: Benign and precancerous endometrial hyperplasias (EH) are differentiated according to two alternative histomorphologic classifications: World Health Organization (WHO) or endometrial intraepithelial neoplasia (EIN) system. The 2017 European Society of Gynaecological Oncology guidelines recommend paired box 2 protein (PAX2) immunohistochemistry to identify precancerous EH. However, methods for interpreting immunostaining and diagnostic accuracy are not defined, and the role of PAX2 in endometrial carcinogenesis is unclear. We aimed to assess: (a) PAX2 expression throughout endometrial carcinogenesis, from normal endometrium to benign EH, precancerous EH, and endometrial cancer (EC); (b) the diagnostic accuracy of PAX2 immunohistochemistry in diagnosing precancerous EH, defining criteria for its use., Material and Methods: Electronic databases were searched for from their inception to July 2018. All studies evaluating PAX2 immunohistochemistry in normal endometrium, EH, and EC were included. Univariate comparisons of PAX2 expression were performed with Fisher's exact test (significant P < .05). Sensitivity, specificity, positive and negative likelihood ratio, diagnostic odds ratio (DOR), and area under the curve on summary receiver operating characteristic curves were calculated. Subgroup analyses were based on expression thresholds (decrease vs complete loss) and classifications used (WHO vs EIN)., Results: Six studies with 266 normal endometrium, 586 EH, and 114 EC were included. Both decrease and complete loss of PAX2 expression were significantly more common in EC and precancerous EH than benign EH. Diagnostic accuracy was moderate for both PAX2 complete loss and decrease (areas under the curve 0.829 and 0.876, respectively). PAX2 complete loss with EIN system showed the best results (sensitivity = 0.72; specificity = 0.95; DOR = 43.13)., Conclusions: PAX2 seems to behave as a tumor suppressor in endometrial carcinogenesis. PAX2 is an accurate marker of precancerous EH; complete loss of PAX2 and EIN classification appear as the optimal diagnostic criteria., (© 2018 Nordic Federation of Societies of Obstetrics and Gynecology.)

The management of patients with a poor ovarian response (POR) to ovarian stimulation represents a challenging issue in reproductive medicine. Apart from economic burdens, the patient with POR has poor prognosis in assisted reproductive technology (ART), which represents a common cause of drop-out from treatment. To introduce a more nuanced picture of POR, the POSEIDON group developed novel criteria to identify and classify patients with low prognosis who undergo ART. The primary goal of POSEIDON criteria is to offer clinicians a pragmatic system to guide therapeutic management with the mindset to obtain the number of oocytes needed for improving ART success. A novel marker of ART success, namely, the ability to obtain the number of oocytes required for achieving at least one euploid embryo for transfer in each patient, is aligned with the POSEIDON criteria. A novel prediction model (ART Calculator) is developed to help clinicians estimate the POSEIDON marker of success. Furthermore, the POSEIDON criteria can also be used to identify more homogeneous populations to test in interventional trials.

Objective: To study the role of recombinant human LH supplementation in women with hypo-response to ovarian stimulation., Methods: We performed a systematic review and meta-analysis of prospective clinical trials in which recombinant FSH monotherapy protocols were compared with LH-supplemented protocols in hypo-responders. A search was conducted of the Scopus, MEDLINE databases without time or language restrictions. Primary outcome was clinical pregnancy rate., Results: Significantly higher clinical pregnancy rates (odds ratio: 2.03, P = 0.003), implantation rates (odds ratio: 2.62, P = 0.004) and number of oocytes retrieved (weight mean differences: 1.98, P = 0.03) were observed in hypo-responders supplemented with recombinant LH versus hypo-responders who underwent FSH monotherapy. No differences in terms of mature oocytes or miscarriage rates were found between the two groups., Conclusion: In conclusion, our analysis confirms that women with a hypo-response to exogenous gonadotropins might benefit from LH supplementation. However, more trials are required before a definitive conclusion can be drawn.

Study Objective: Angular pregnancy is a rare and life-threatening condition in which the embryo is implanted in the lateral angle of the uterine cavity, medial to the uterotubal junction and round ligament. Angular pregnancy is associated with a high risk of uterine rupture of about 23% [1]. No consensus has been achieved regarding the diagnostic and therapeutic approach of angular pregnancy [2]. Thus, the aim of this study was to report a case of hysteroscopic treatment of an angular pregnancy in a 34-year-old women., Design: Step-by-step video presentation of the surgical treatment (Canadian Task Force classification III)., Setting: Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine, University of Naples Federico II, Naples, Italy., Patient: A 34-year-old woman. Written informed consent was obtained from the patient., Intervention: Hysteroscopy., Measurements and Main Results: A 34-year-old woman was admitted to our Department with pelvic pain at 6 weeks of gestation. β-Human chorionic gonadotropin (β-hCG) was 5331 mIU/mL. The transvaginal ultrasound showed a gestational sac of 15 × 11 mm in the left uterine angle of an embryo without cardiac activity. The woman opted for a conservative approach with multiple-dose methotrexate [3]. Five days later the β-hCG increased to 7589 mIU/mL with no regression of pregnancy at the transvaginal ultrasound. Therefore, a surgical approach was offered to the patient [4,5]. Laparoscopy showed normal salpinges, whereas hysteroscopy identified the gestational sac in the left uterine angle. A 5Fr bipolar electrode was used to open the gestational capsular decidua. The chorionic villi were progressively separated from the implantation site. Using grasping forceps we removed the specimen for histologic examination. Histologic examination confirmed the diagnosis of angular pregnancy. On the second postoperative day β-hCG was 1131 mIU/mL, and the patient was discharged the day after. At the 1-month follow-up visit, β-hCG and transvaginal ultrasound were negative for pregnancy. The office hysteroscopy showed an empty uterine cavity at 3-months' follow-up., Conclusion: Our case shows that hysteroscopy may be used as a diagnostic and therapeutic tool for angular pregnancy, providing a unique image of the intact removal of the gestational sac., (Copyright © 2018 American Association of Gynecologic Laparoscopists. Published by Elsevier Inc. All rights reserved.)

Air pollution is a cause of concern for human health. For instance, it is associated with an increased risk for cancer, cardiovascular and respiratory disorders. In vitro and in vivo studies suggested that air pollutants could act as endocrine disruptors, promote oxidative stress and exert genotoxic effect. Whether air pollution affects female infertility is under debate. The aim of the present study was to conduct a systematic review of studies that evaluated the impact of air pollution on female infertility. We systematically searched the MEDLINE (PubMed) and SCOPUS databases to identify all relevant studies published before October 2017. No time or language restrictions were adopted, and queries were limited to human studies. We also hand-searched the reference lists of relevant studies to ensure we did not miss pertinent studies. The risk of bias and quality assessment of the studies identified were performed using the Newcastle-Ottawa Scale. Primary outcomes were conception rate after spontaneous intercourse and live birth rate after in vitro fertilization (IVF) procedures. Secondary outcomes were first trimester miscarriage, stillbirths, infertility, number of oocytes and embryo retrieved. Eleven articles were included in the analysis. We found that in the IVF population, nitrogen dioxide and ozone were associated with a reduced live birth rate while particulate matter of 10 mm was associated with increased miscarriage. Furthermore, in the general population, particulate matter of 2.5 mm and between 2.5 and 10 mm were associated with reduced fecundability, whereas sulfur dioxide , carbon monoxide and nitrogen dioxide might promote miscarriage and stillbirths. The main limitation of our findigns resides in the fact that the desegn of studies included are observational and retrospective. Furthermore, there was a wide heterogenity among studies. Although larger trials are required before drawing definitive conclusions, it seems that air pollution could represent a matter of concern for female infertility.

Introduction: Endometrial hyperplasia is differentiated into benign or premalignant. Two histological classifications are used for this purpose: World Health Organization (WHO) classification, based on cytological atypia, disregarding glandular complexity, and endometrial intraepithelial neoplasia (EIN) classification, based on several different parameters. B-cell lymphoma 2 (Bcl-2) loss has been studied as immunohistochemical marker with the aim of improving the differential diagnosis between benign and premalignant hyperplasia. We aimed to evaluate: (A) Bcl-2 loss as marker of endometrial precancer, by assessing it in proliferative endometrium, benign hyperplasia, premalignant hyperplasia, and endometrial cancer; (B) the diagnostic accuracy of Bcl-2 in the differential diagnosis between benign and premalignant endometrial hyperplasia; (c) how the results change according to the histological classification and the thresholds of Bcl-2 expression used., Material and Methods: Electronic databases were searched from their inception to March 2018. All studies assessing Bcl-2 immunohistochemistry in endometrial specimens were included., Results: In total, 20 observational studies assessing 1,278 specimens were included. Bcl-2 loss rates were not significantly different between proliferative endometrium and benign hyperplasia (P = 0.12) and between premalignant hyperplasia and endometrial cancer (P = 0.53). Among hyperplasias, Bcl-2 loss was significantly associated with premalignancy, according to both the WHO (OR = 4.39; P < 0.00001) and EIN classifications (OR = 6.07; P = 0.01), and also with architecture complexity (OR = 2.06; P = 0.02). Using the WHO classification, Bcl-2 loss showed low diagnostic accuracy in detecting premalignant hyperplasia (area under the curve [AUC] = 0.708), with a sensitivity of 0.41, a specificity of 0.81, a positive likelihood ratio of 3.22, and a negative likelihood ratio of 0.69. Using the EIN classification, accuracy was high (AUC = 0.938), with a sensitivity of 0.18, a specificity of 0.97, a positive likelihood ratio of 5.16 and a negative likelihood ratio of 0.86. Thresholds of Bcl-2 expression not involving a complete loss showed lower diagnostic accuracy with a slight increase in sensitivity, but a severe decrease in specificity., Conclusions: B-cell lymphoma 2 loss is a marker of endometrial precancer, with a high specificity and high diagnostic accuracy if the EIN classification is used. Thresholds of Bcl-2 expression not involving a complete loss should not be considered. Bcl-2 loss in endometrial hyperplasia may be a novel indication for treatment when precancerous features are ambiguous in a histological examination. Bcl-2 loss correlates better with EIN classification than with the WHO classification, suggesting that glandular complexity is an important precancerous feature., (© 2018 Nordic Federation of Societies of Obstetrics and Gynecology.)

Objective: Several markers have been studied to predict the responsiveness of endometrial hyperplasia (EH) and early endometrial cancer (EEC) to progestin therapy. PTEN has played a major role in this field, although its predictive significance is still undefined. We aimed to assess if loss of PTEN expression on pre-treatment endometrial specimen may be a predictive markers of response to progestins in EH and EEC., Study Design: MEDLINE, EMBASE, Web of Sciences, Scopus, ClinicalTrial.gov, OVID and Cochrane Library were searched for relevant articles from the inception to May 2018. All studies assessing PTEN expression as predictive marker in EH and EEC treated with progestin were included. Relative risk (RR) for therapy failure was calculated with 95% confidence interval (CI) and a significant p-value<0.05, with a subgroup analysis based on the histologic category (EEC or EH) and the administration route of progestin (oral or intrauterine)., Results: Seven cohort studies assessing 376 patients were included. PTEN loss was not significantly associated with the outcome of therapy in the overall analysis (RR = 1.24, 95% CI, 0.88-1.76, p = 0.21), in + the subgroups of EEC (RR = 0.89, 0.32-2.49, p = 0.83), EH (RR = 1.30, 0.90-1.87 p = 0.16), oral progestin (RR = 1.25 0.88-1.79, p = 0.22) and intrauterine device (RR = 1.02, 0.36-2.87, p = 0.97)., Conclusion: PTEN seems not to be useful as predictive marker of response to the conservative treatment of EH and EC, regardless of the administration route (oral or intrauterine) of progestins. We advise future researcher not to further assess PTEN as a stand-alone predictive marker., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Morcellation of undiagnosed uterine sarcoma is cause of abdominal/pelvic dissemination, residual tumor and recurrence. In the preoperative evaluation of suspect uterine masses, magnetic resonance imaging (MRI) and serum lactate dehydrogenase (LDH) total activity are referred to as the most effective tools, while computed tomography scan (CT) and LDH isoenzymes are less considered in literature., Case Presentation: A 46 year old woman was admitted to our department with a large uterine mass. Ultrasonography, MRI and LDH total activity did not allow a diagnosis of malignancy, and the woman expressed the wish to avoid hysterectomy. In spite of this, we opted for a total abdominal hysterectomy instead of a laparoscopic myomectomy, due to an elevation of LDH5/LDH1 ratio and CT findings indicative of sarcoma. Histological examination revealed a high grade leiomyosarcoma, confirming our suspicion. Thus, we had avoided the risks linked to morcellation., Conclusions: Our experience suggests that LDH isoenzymes assessment may be relevant in preoperative diagnosis of uterine sarcoma. Further studies are necessary to determine its role in a diagnostic algorithm. We think it may be useful especially for patients with clinical or ultrasonographic suspicion of uterine sarcoma not confirmed by imaging techniques. Furthermore, the role of less considered imaging techniques, such as CT, should not be underestimated in challenging cases.

Hypo-responsiveness to controlled ovarian stimulation is an undervalued topic in reproductive medicine. This phenomenon manifests as a low follicles output rate (FORT) with a discrepancy between the relatively low number of pre-ovulatory follicles which develop following ovarian stimulation as compared to the number of antral follicles available at the start of stimulation. The pathophysiology mechanisms explaining the ovarian resistance to gonadotropin stimulation are not fully understood, but the fact that both hypo-responders and normal responders share similar phenotypic characteristics suggests a genotype-based mechanism. Indeed, existing evidence supports the association between specific gonadotropin and their receptor polymorphisms and ovarian hypo-response. Apart from genotypic trait, environmental contaminants and oxidative stress might also be involved in the hypo-response pathogenesis. The ratio between the number of oocytes collected at the ovum pick up and the number of antral follicles at the beginning of OS [Follicle to oocyte index (FOI)] is proposed as a novel parameter to assess the hypo-response. Compared with traditional ovarian reserve markers, FOI might reflect most optimally the dynamic nature of follicular growth in response to exogenous gonadotropin. In this review, we contextualize the role of FOI as a parameter to identify this condition, discuss the underlying mechanisms potentially implicated in the pathogenesis of hypo-response, and appraise possible the treatment strategies to overcome hyper-responsiveness to gonadotropin stimulation.

Background: Genotype has been implicated in the outcome of ovarian stimulation. The analysis of patient-specific genotypes might lead to an individualized pharmacogenomic approach to controlled ovarian stimulation (COS). However, the validity of such an approach remains to be established., Objective and Rationale: To define the impact of specific genotype profiles of follicle-stimulating hormone, luteinizing hormone and their receptors (FSHR, LHR and LHCGR) on ovarian stimulation outcome. Specifically, our aim was to identify polymorphisms that could be useful in clinical practice, and those that need further clinical investigation., Search Methods: A systematic review followed by a meta-analysis was performed according to the Cochrane Collaboration and Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines without time restriction. We searched the PubMed/MEDLINE, Cochrane Library, SCOPUS and EMBASE databases to identify all relevant studies published before January 2017. Only clinical trials published as full-text articles in peer-reviewed journals were included. The primary outcome was the number of oocytes retrieved., Outcomes: Fifty-seven studies were assessed for eligibility, 33 of which were included in the qualitative and quantitative analyses. Data were independently extracted using quality indicators. COS outcomes related to seven polymorphisms (FSHR [rs6165], FSHR [rs6166], FSHR [rs1394205], LHB [rs1800447], LHB [rs1056917], LHCGR [rs2293275] and LHCGR [rs13405728]) were evaluated. More oocytes were retrieved from FSHR (rs6165) AA homozygotes (five studies, 677 patients, weighted mean difference [WMD]: 1.85, 95% CI: 0.85-2.85, P < 0.001; I2 = 0%) than from GG homozygotes and AG heterozygotes (four studies, 630 patients, WMD: 1.62, 95% CI: 0.28-2.95, P = 0.020; I2 = 56%). Moreover, stimulation duration was shorter in FSHR (rs6165) AA homozygotes than in AG carriers (three studies, 588 patients, WMD -0.48, 95% CI: -0.87 to -0.10, P = 0.010, I2 = 44%). A higher number of oocytes (21 studies, 2632 patients WMD: 0.84, 95% CI: 0.19 to 1.49, P = 0.01, I2 = 76%) and metaphase II oocytes (five studies, 608 patients, WMD: 1.03, 95% CI: 0.01-2.05, P = 0.050, I2 = 0%) was observed in AA than in GG homozygote carriers. FSH consumption was significantly lower in FSHR (rs1394205) GG homozygotes (three studies, 411 patients, WMD: -1294.61 IU, 95% CI: -593.08 to -1996.14 IU, P = 0.0003, I2 = 99%) and AG heterozygotes (three studies, 367 patients, WMD: -1014.36 IU, 95% CI: -364.11 to -1664.61 IU, P = 0.002, I2 = 99%) than in AA homozygotes., Wider Implications: These results support the clinical relevance of specific genotype profiles on reproductive outcome. Further studies are required to determine their application in a pharmacogenomic approach to ovarian stimulation.

Objective: Vulvovaginal atrophy (VVA) is a condition frequently observed in menopause. Its symptoms can significantly affect the quality of life of patients. Since VVA is related to estrogen deficiency, chemotherapy and hormone therapy for breast cancer (BC) might cause VVA by inducing menopause. Given the lack of effective treatment for VVA in BC survivors, we retrospectively evaluated the efficacy and tolerability of fractional microablative CO2 laser therapy in these patients., Methods: We treated 82 BC survivors with three cycles of CO2 laser after failure of topical nonestrogenic therapy. The severity of symptoms was assessed with a visual analog scale (VAS) at baseline and after completion of laser therapy. Differences in mean VAS scores of each symptom before and after treatment were assessed with multiple t tests for pairwise comparisons. Multivariate analyses were used to adjust the final mean scores for the main confounding factors., Results: Pre versus post-treatment differences in mean VAS scores were significant for sensitivity during sexual intercourse, vaginal dryness, itching/stinging, dyspareunia and dysuria (P < 0.001 for all), bleeding (P = 0.001), probe insertion (P = 0.001), and movement-related pain (P = 0.011). Multivariate analyses confirmed that results were significant, irrespective of patients' age and type of adjuvant therapy., Conclusion: This study shows that CO2 laser treatment is effective and safe in BC patients with iatrogenic menopause. However, the optimal number of cycles to administer and the need for retreatment remain to be defined. Prospective trials are needed to compare CO2 laser therapy with therapeutic alternatives.

Objective: The application of an electronic database in clinical practice is used widespread in every field of medicine. The aim of the present study is to illustrate our experience to use a database software for documentation of two of our clinical activities, outpatient hysteroscopy and inpatient gynaecological surgery., Patients and Methods: In 2004, we designed two databases, the first one to document surgical procedures in the operating theatre, the second to document outpatient hysteroscopy procedures using FileMaker v.8.5. The data entry interface contains free text fields for patient demographic data and the description of the surgical procedure, supplemented by drop-down lists for items such as clinical findings, procedures, instrumentation, technique, and complications. Copies were filed in the main hospital notes, sent to General Practitioners, and also given to our patients., Results: Since August 2004, we have used our two databases to document 2766 gynaecological operations and 3777 outpatient hysteroscopies. All users particularly liked the dropdown lists as their use greatly reduced the time taken to enter each patient's data. The databases were regularly used to select patients for audit projects and research data collection for prospective studies., Conclusions: FileMaker is an user-friendly and easily configured software, extremely valuable in everyday clinical work.

Objective: To assess the role of recombinant human LH (r-hLH) supplementation in ovarian stimulation for ART in specific subgroups of patients., Design: Systematic review., Setting: Centers for reproductive care., Patient(s): Six populations were investigated: 1) women with a hyporesponse to recombinant human FSH (r-hFSH) monotherapy; 2) women at an advanced reproductive age; 3) women cotreated with the use of a GnRH antagonist; 4) women with profoundly suppressed LH levels after the administration of GnRH agonists; 5) normoresponder women to prevent ovarian hyperstimulation syndrome; and 6) women with a "poor response" to ovarian stimulation, including those who met the European Society for Human Reproduction and Embryology Bologna criteria., Intervention(s): Systematic review., Main Outcome Measure(s): Implantation rate, number of oocytes retrieved, live birth rate, ongoing pregnancy rate, fertilization rate, and number of metaphase II oocytes., Result(s): Recombinant hLH supplementation appears to be beneficial in two subgroups of patients: 1) women with adequate prestimulation ovarian reserve parameters and an unexpected hyporesponse to r-hFSH monotherapy; and 2) women 36-39 years of age. Indeed, there is no evidence that r-hLH is beneficial in young (<35 y) normoresponders cotreated with the use of a GnRH antagonist. The use of r-hLH supplementation in women with suppressed endogenous LH levels caused by GnRH analogues and in poor responders remains controversial, whereas the use of r-hLH supplementation to prevent the development of ovarian hyperstimulation syndrome warrants further investigation., Conclusion(s): Recombinant hLH can be proposed for hyporesponders and women 36-39 years of age., (Copyright © 2018 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To compare the perinatal outcomes of singleton pregnancies resulting from blastocyst- vs cleavage-stage embryo transfer and to assess whether they differ between fresh and frozen embryo transfer cycles., Methods: A systematic review of the literature was carried out using the Scopus, MEDLINE and ISI Web of Science databases with no time restriction. We included only peer-reviewed articles involving humans, in which perinatal outcomes of singleton pregnancies after blastocyst-stage embryo transfer were compared with those after cleavage-stage embryo transfer. Primary outcomes were preterm birth before 37 weeks and low birth weight (< 2500 g). Secondary outcomes were very preterm birth before 32 weeks, very low birth weight (< 1500 g), small-for-gestational-age (SGA), large-for-gestational-age (LGA), perinatal mortality and congenital anomaly. A meta-analysis was performed using a random-effects model. Three subgroups were evaluated: fresh only, frozen only and fresh plus frozen embryo transfer cycles., Results: From a total of 3928 articles identified, 14 were selected for qualitative/quantitative analysis. Significantly higher incidences of preterm birth < 37 weeks (11 studies, n = 106 629 participants; risk ratio (RR), 1.15 (95% CI, 1.05 - 1.25); P = 0.002) and very preterm birth < 32 weeks (seven studies, n = 103 742; RR, 1.16 (95% CI, 1.02-1.31); P = 0.03) were observed after blastocyst- than after cleavage-stage embryo transfer in fresh cycles. However, the risk of preterm and very preterm birth was similar after blastocyst- and cleavage-stage transfers in frozen and fresh plus frozen cycles. Overall effect size analysis revealed fewer SGA deliveries after blastocyst- compared with cleavage-stage transfer in fresh cycles but a similar number in frozen cycles. Conversely, more LGA deliveries were observed after blastocyst- compared with cleavage-stage transfer in frozen cycles (two studies, n = 39 044; RR, 1.18 (95% CI, 1.09-1.27); P < 0.0001) and no differences between the two groups in fresh cycles (four studies, n = 42 982; RR, 1.14 (95% CI, 0.97-1.35); P = 0.11). There were no differences with respect to low birth weight, very low birth weight or congenital anomalies between blastocyst- and cleavage-stage transfers irrespective of the cryopreservation method employed. Only one study reported a higher incidence of perinatal mortality after blastocyst- vs cleavage-stage embryo transfer in frozen cycles, while no differences were found in fresh cycles., Conclusions: Our results suggest that cryopreservation of embryos can influence outcome of pregnancy conceived following blastocyst- vs cleavage-stage embryo transfer in terms of preterm birth, very preterm birth, LGA, SGA and perinatal mortality. Caution should be exercised in interpreting these findings given the low level of evidence and wide heterogeneity of the studies. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd., (Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.)

Objective: To evaluate the hormonal profile in three breast cancer patients who underwent controlled ovarian stimulation in the presence of the aromatase inhibitor letrozole., Patients and Methods: In IVF University referral center, a case series of three breast cancer patients who underwent controlled ovarian stimulation (COS) with recombinant FSH and letrozole were investigated. Ovulation was induced with hCG (case No. 1) or with GnRH agonist (case No. 2-3). The primary outcome of our study was the detection of progesterone levels in the luteal phase., Results: Very high progesterone values (mean 186.6 ± 43.6 ng/mL) during the luteal phase were recorded in all three cases., Conclusions: High progesterone levels can be related to the use of letrozole independently of the most commonly used trigger regimen. Although progesterone has long been considered a protective factor against breast cancer, several studies have demonstrated that progesterone could expand a transformation-sensitive stem cell population in the mammary glands. The estrogen negative feedback effect on the hypothalamus-pituitary axis and the disruption of steroid biosynthesis and could represent an intriguing reason behind this phenomenon. Our results highlight the need to evaluate further the increase in progesterone levels in the luteal phase in women with breast cancer undergoing COS with letrozole.

Introduction: Although insulin resistance plays an important pathogenetic role in polycystic ovary syndrome (PCOS), no correlation between ultrasound PCOS pattern and insulin resistance has yet been reported. The aim of this retrospective observational study was to assess whether the ovarian ultrasonographic parameter differed between PCOS women with insulin resistance and those with a hyperandrogenic profile., Materials and Methods: Women who fulfilled the Rotterdam criteria for PCOS were retrospectively studied. Anthropometric, biochemical, and clinical data were recorded. Women were divided into two groups based on specific transvaginal ultrasound parameters: subjects with more than half of the follicles measuring between 5 and 9 mm in diameter, an ultrasonographic determined stroma/total area (S/A) > 0.34 and a "necklace" sign of antral follicles (Group A); and subjects with more than half of the antral follicles measuring between 2 and 4 mm in diameter, an S/A ≤ 0.34; no "necklace" sign but ubiquitously distributed follicles determined by ultrasound (Group B). The association between these ultrasound patterns and the presence of insulin resistance was also evaluated., Results: Seventy-eight patients were enrolled: 33 with ultrasound sound pattern A and 45 with pattern B. The latter pattern had a sensitivity of 88% and a specificity of 78% in predicting PCOS women with insulin resistance. There were no differences in age, Ferriman-Gallwey score, and serum gonadotropin or androgen levels between the two groups. Body mass index, the waist-to-hip ratio, and homeostasis model assessment were significantly higher in group B than in group A ( p  < 0.05). Conversely, sex hormone binding globulin levels and ovarian volume were significantly higher in group A ( p  < 0.05). Insulin resistance was more frequent in group B than in group A (36/41, 87.8% versus 7/32, 21.8%; p  < 0.05)., Conclusion: These results suggest that insulin resistance could be associated with a specific ultrasound pattern in PCOS patients.

Objective: The use of gonadotropin-releasing hormone agonist for ovulation triggering has become an intriguing topic in the last few years. As long as adequate luteal phase support is provided, it may be a valuable alternative to standard hCG triggering, associated with a significant reduction in OHSS incidence. Several luteal phase support options have been proposed, but few studies have addressed the issue of the appropriate route for progesterone administration to women triggered with GnRHa. The aim of the study was to evaluate the effect of GnRHa triggering on IVF/ICSI outcomes, using modified luteal phase support with intramuscular progesterone., Patients and Methods: A retrospective study was carried out between January 2014 and December 2015, comparing the reproductive outcome in GnRHa triggered women given modified luteal phase support with intramuscular progesterone (Group A) with the outcome in women triggered with standard hCG (Group B) in IVF/ICSI cycles., Results: 200 (Group A n = 100; Group B n = 100) consecutive normoresponder women were included. No differences with respect to Age, BMI, basal FSH, basal Estradiol and infertility diagnosis were observed between groups. Increased numbers of retrieved oocytes (8.1 ± 3.3 versus 6.8 ± 3.5, p = 0.009) and mature oocytes (5.8 ± 2.6 versus 5.1 ± 2.7, p = 0.03) were detected in Group A compared with Group B. Implantation, biochemical pregnancy and ongoing pregnancy rates were similar., Conclusions: Our findings confirmed that the GnRHa triggering strategy is associated with increased number of oocytes retrieved and of mature oocytes even in normoresponder women. Moreover, in these patients, the use of intramuscular progesterone during luteal phase support achieved satisfactory IVF outcomes.

Objectives: Breast cancer is one of the most common malignancies in women. Hormonal treatment and chemotherapy induce a transient or permanent menopause status. Vulvovaginal atrophy (VVA) is a frequent debilitating symptom of menopause that is best treated with local or systemic estrogen formulations. Because estrogens drive the growth of the majority of breast cancers, most effective VVA therapies are precluded. The aim of this study was to evaluate the effects of fractional microablative CO2 laser on sexual function and in relieving symptoms in women with breast cancer and VVA induced or exacerbated by iatrogenic menopause., Methods: This retrospective study included 26 women affected by hormone-receptor positive breast tumors and treated for VVA symptoms with the fractional microablative CO2 laser system. Every 30 to 40 days, women underwent a cycle of treatment for a total of three cycles. During each cycle, women underwent a gynecological examination and completed visual analog scale questionnaires designed to assess (1) the degree of symptoms and (2) procedure-related discomfort., Results: Treatment resulted in a significant regression of VVA symptoms and procedure-related discomfort versus baseline (P < 0.001 in almost all cases). No adverse reactions were observed nor reported by women., Conclusions: Fractional microablative CO2 laser treatment is associated with a significant improvement of VVA symptoms in women affected by hormone-driven breast cancer. This procedure has the advantage of relieving iatrogenic/physiological VVA symptoms without resorting to contraindicated estrogen preparations, which have been the most effective therapy thus far.

It has been reported that 10% to 15% of young normogonadotrophic women show suboptimal response to standard gonadotropin-releasing hormone-a long protocol. These patients require higher doses of exogenous follicle-stimulating hormone (FSH). This phenomenon could be associated with genetic characteristics. In this study, FSH receptor polymorphism was retrospectively evaluated in 42 normoresponder young women undergoing an in vitro fertilization/intracytoplasmic sperm injection cycle; patients were stratified according to recombinant human FSH (r-hFSH) consumption. We selected 17 normoresponder young patients who required a cumulative dose of recombinant FSH (rFSH) >2500 UI (group A). A control group was randomly selected among patients who required a cumulative dose of rFSH <2500 UI (group B). Follicle-stimulating hormone receptor (FSH-R) 307Ala and 680Ser variants were analyzed in all our patients. Our results show that the mean number of rFSH vials (36.3 ± 7.5 vs 28.6 ± 4.5, P = .0001) and days of stimulation (12.7 ± 2.4 vs 10.8 ± 2.8, P = .03) were significantly lower in group B, whereas the number of oocytes retrieved (7.1 ± 1.5 vs 9.6 ± 2.4; P = .0005) and the average number of embryos transferred (2.1 ± 0.7 vs 2.7 ± 0.4; P = .001) were significantly lower in group A. Estradiol serum levels on the human chorionic gonadotrophin day were significantly lower in group A (997.8 ± 384.9 pg/mL vs 1749.1 ± 644.4; P = .0001). The incidence of the Ser/Ser genotype was higher in patients with higher r-hFSH consumption (group A; P = .02). Based on our results, we hypothesize an association between the FSH-R polymorphisms and a "hyporesponse" to exogenous FSH., (© The Author(s) 2016.)

Background: The scientific community has been re-evaluating the clinical relevance of hysteroscopy in the diagnosis and treatment of uterine factors and its role in the infertility work-up, thanks to its potential capability to improve reproductive outcomes and reduce time to pregnancy., Objective and Rationale: The objective of this systematic review and meta-analysis was to assess the efficacy of diagnostic and operative hysteroscopy in improving the live birth rate (LBR) of infertile women, with and without intrauterine abnormalities, at any stage of the infertility work-up., Search Methods: PubMed, Embase, the Cochrane Library and the Clinical Trials Registry using Medical Subject Headings and free text terms were searched up to June 2014, without language or year restrictions. Randomized controlled trials (RCTs) enrolling infertile women with no suspected intrauterine cavity abnormalities and comparing hysteroscopy versus no hysteroscopy at any stage of the diagnostic work-up, but prior to the first attempt of standard IVF or ICSI or after (one or more) failed attempts of IVF/ICSI were included. RCTs enrolling infertile women with intrauterine abnormalities and comparing operative versus diagnostic hysteroscopy were also included. Risk of bias was assessed using the criteria recommended by the Cochrane Collaboration and the overall quality of evidence was assessed using the GRADE approach. Results were pooled by meta-analysis using the random effect model., Outcomes: The primary outcome evaluated was the LBR, while secondary outcomes were pregnancy rate, miscarriage rate and procedure-related complications. Five hundred and eighty-eight records were retrieved after removing duplicates. Nine studies were included, with 2976 participants. Four studies included infertile women with one or more failed IVF/ICSI cycles. Two studies included infertile women who were candidates for their first IVF/ICSI. One study included candidates both for first IVF/ICSI and with one or more failed IVF/ICSI cycles. Two studies included infertile women affected by uterine fibroids and endometrial polyps, who had not received IVF/ICSI nor were candidates. Seven studies were included in the meta-analysis. Comparing hysteroscopy with no hysteroscopy prior to any (first or subsequent) IVF/ICSI attempt in infertile women without intrauterine abnormalities, there was very low-quality evidence that hysteroscopy increased LBR (relative risk (RR) 1.48, 95% confidence interval (CI) 1.20-1.81; three studies with 1088 participants) and moderate quality evidence that it increased pregnancy rate (RR 1.45, 95% CI 1.26-1.67; seven studies, 2545 participants). Results on pregnancy rate were confirmed in the subgroup analysis of five studies including only women with one or more implantation failures (RR 1.41, 95% CI 1.14-1.75) and three studies where hysteroscopy was performed before the first IVF/ICSI attempt (RR 1.55, 95% CI 1.26-1.91). Comparing operative hysteroscopy for intrauterine abnormalities in infertile women with already diagnosed polyps or fibroids, there was low-quality evidence that operative hysteroscopy increases pregnancy rate (RR 2.13, 95% CI 1.56-2.92). None of the studies comparing operative versus diagnostic hysteroscopy assessed LBR., Wider Implications: Robust and high-quality RCTs are still needed before hysteroscopy can be regarded as a first-line procedure in all infertile women, especially during the basal clinical assessment of the couple, when assisted reproductive treatment is not indicated yet., (© The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Little is known about the impact of weight loss interventions on pregnancy rate. A systematic review with meta-analysis of literature has been performed to evaluate the incidence of successful pregnancy after bariatric interventions in infertile women. By pooling together data from 589 infertile obese women, we have been able to provide an aggregate estimation of successful pregnancy after weight loss interventions. Our results showed an impressive high incidence (58%) of infertile women who become spontaneously pregnant after surgery. Based on our results, bariatric interventions could be included in the treatment of obesity-related infertility. However, the results must be interpreted with caution owning to the quality of the data provided by included studies. Further ad hoc studies are needed to validate the effectiveness of bariatric interventions on reproductive function.

Both oxidative stress and polycystic ovary syndrome have been involved in several aspects of female reproduction. In this retrospective observational study, the outcome of controlled ovarian stimulation and follicular microenvironment of twenty-five women affected by PCOS (Group A) have been explored, evaluating the effects of myo-inositol in association with antioxidant activities (FT500 Plus(®)). Twenty-five untreated-PCOS women (Group B) with similar characteristics served as control group. Although there was no difference in ovarian volume at time zero, this parameter was significantly smaller at the 5-month follow-up in the Group A (11.1±0.9 versus 13.5±1; P=0.0001). Group A showed a significant increase in the number of MII oocytes (6.3±2.5 versus 4.5±2; P=0.03) and glutathione peroxidase activity in follicular fluid (15.4±6.2 versus 11±2.2; P=0.04). FT500 Plus(®) may be considered in PCOS patient for improving oocyte quality., (Copyright © 2015 Elsevier Inc. All rights reserved.)